@article{a99c2831577f4c2f8ff356b6295bf4f8,
title = "Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients",
abstract = "Purpose: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). Experimental design: In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). Results: Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 months with monotherapy versus 2.8/11.8 months with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p < 0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9 months for monotherapy versus 2.8/13.1 months for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 103/mm3). Conclusions: In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.",
keywords = "HDAC, Hepatocellular carcinoma, Resminostat, Sorafenib, Systemic chemotherapy",
author = "Tak, {Won Young} and Ryoo, {Baek Yeol} and Lim, {Ho Yeong} and Kim, {Do Young} and Takuji Okusaka and Masafumi Ikeda and Hisashi Hidaka and Yeon, {Jong Eun} and Eishiro Mizukoshi and Manabu Morimoto and Lee, {Myung Ah} and Kohichiroh Yasui and Yasunori Kawaguchi and Jeong Heo and Sojiro Morita and Kim, {Tae You} and Junji Furuse and Kazuhiro Katayama and Takeshi Aramaki and Rina Hara and Takuya Kimura and Osamu Nakamura and Masatoshi Kudo",
note = "Funding Information: Conflict of interest Won Young Tak has served as a compensated consultant/advisor for Bayer HealthCare Pharmaceuticals Inc., Gilead Science Korea Ltd., AbbVie Ltd., Ono Pharma Korea Co., Ltd., Eisai Korea Inc., and Bukwang Pharmaceutical Co., Ltd. He has also received research grant support from Samil Pharm Co., Ltd. as well as honoraria from Bayer Korea Ltd., MSD Korea Ltd., Gilead Science Korea Ltd., AbbVie Ltd., Samil Pharm Co., Ltd., and Yuhan Co., Ltd. Funding Information: Masatoshi Kudo has received honoraria from Bayer, Eisai, MSD, and Ajinomoto. He has served as a compensated consultant/advisor for Bayer, Eisai, Kowa, MSD, BMS, Chugai, and Taiho. Furthermore, he has received research grant support from Daiichi Sankyo, Medico{\textquoteright}s Hirata, Otsuka, Taiho, Astellas Pharma, Chugai, Abbvie, Bristol-Myers Squibb, Takeda, MSD, Eisai, Sumitomo Dainippon, and Bayer. Funding Information: This study was supported by Yakult Honsha Co., Ltd. Funding Information: Kazuhiro Katayama has received speaker{\textquoteright}s bureau honorarium from Ajinomoto, Otsuka, Chugai, MSD, Bristol-Myers, Daiichi-Sankyo, Bayer, Nobelpharma Co., Ltd. He has also received research grant support from Bayer, Asuka, Kowa, and Bristol-Meyers. Publisher Copyright: {\textcopyright} 2018, Springer Science+Business Media, LLC, part of Springer Nature.",
year = "2018",
month = dec,
day = "1",
doi = "10.1007/s10637-018-0658-x",
language = "English",
volume = "36",
pages = "1072--1084",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "6",
}